GA: Cross-linking of hyaluronic acid modified by a strained alkyne with a photosensitive crosslinker terminating in azides gives hydrogels with tuneable mechanical properties. By tuning the wavelength of employed light, the hydrogel can either be fully degraded allowing harvesting of cultured cells or softened resulting in notable changes in cell morphology.

Properties of semisynthetic hydrogels can be fine-tuned, making these attractive for various applications in regenerative medicine. Herein, a hydrogel platform based on hyaluronic acid (HA) modified by (1R, 8S,9S)-bicycle[6.1.0]non-4-yn-9-ylmethanol (BCN) and a cross-linker composed of light-sensitive o-nitrobenzyl and polyethylene glycol (PEG) chains terminating in azides is described. The two components can undergo strain-promoted azide–alkyne cycloaddition resulting in rapid gel formation. First, adipose-derived mesenchymal stromal cells (MSCs) are incorporated in the hydrogel and it is demonstrated that the cells can be easily retrieved by UV light-mediated degradation, maintaining viability and retaining spindle-like shape when the cells are replated. Next, a proof-of-concept of inducing light-mediated softening of the hydrogel to modulate the morphology of the encapsulated cells is provided. A co-culture of endothelial cells (cord blood-derived endothelial colony forming cells and bone marrow-derived MSCs), which is commonly studied for their ability to form capillary-like vascular networks, is cultured in the regular and light-induced softened hydrogels. Nonphotoexposed hydrogels show cells with a prevalently rounded morphology, whereas stretched cells connecting into a primitive capillary network are observed in the light-softened hydrogels. Photo-induced softening offers potential to locally control cell shape and self-organization capacity.